Development of the neuromuscular junction

Witzemann, Veit

doi:10.1007/s00441-006-0237-x

Cited by 118 publications

(105 citation statements)

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“…This neonatal peak in GS activity coincides with the period of terminal differentiation and nerve-induced growth of the myotubes (32). Because glutamine transport in skeletal muscle is electrogenic and dependent on innervation (33), the decline in GS activity may well reflect an innervation-dependent increase in the intracellular concentration of glutamine (34), which is known to decrease the halflife of GS protein (4 -6, 35).…”

Section: Discussionmentioning

confidence: 99%

Glutamine Synthetase in Muscle Is Required for Glutamine Production during Fasting and Extrahepatic Ammonia Detoxification

Hakvoort

Köhler³

et al. 2010

Journal of Biological Chemistry

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The main endogenous source of glutamine is de novo synthesis in striated muscle via the enzyme glutamine synthetase (GS). The mice in which GS is selectively but completely eliminated from striated muscle with the Cre-loxP strategy (GS-KO/M mice) are, nevertheless, healthy and fertile. Compared with controls, the circulating concentration and net production of glutamine across the hindquarter were not different in fed GS-KO/M mice. Only a ϳ3-fold higher escape of ammonia revealed the absence of GS in muscle. However, after 20 h of fasting, GS-KO/M mice were not able to mount the ϳ4-fold increase in glutamine production across the hindquarter that was observed in control mice. Instead, muscle ammonia production was ϳ5-fold higher than in control mice. The fasting-induced metabolic changes were transient and had returned to fed levels at 36 h of fasting. Glucose consumption and lactate and ketone-body production were similar in GS-KO/M and control mice. Challenging GS-KO/M and control mice with intravenous ammonia in stepwise increments revealed that normal muscle can detoxify ϳ2.5 mol ammonia/g muscle⅐h in a muscle GS-dependent manner, with simultaneous accumulation of urea, whereas GS-KO/M mice responded with accumulation of glutamine and other amino acids but not urea. These findings demonstrate that GS in muscle is dispensable in fed mice but plays a key role in mounting the adaptive response to fasting by transiently facilitating the production of glutamine. Furthermore, muscle GS contributes to ammonia detoxification and urea synthesis. These functions are apparently not vital as long as other organs function normally.Glutamine is among the most abundant free amino acids in mammals. Almost 90% of the daily glutamine production originates from endogenous sources, because 30 -35% of all nitrogen derived from protein catabolism is transported in the form of glutamine (1, 2). This glutamine can serve, after transport via the vasculature, as an oxidative fuel for enterocytes and immune cells, a precursor for purine and pyrimidine synthesis, a modulator of protein turnover, or an intermediate for gluconeogenesis and acid-base balance. The only enzyme capable of glutamine synthesis is glutamine synthetase (L-glutamate: ammonia ligase (ADP); EC 6.3.1.2). Because of the prominent role of glutamine in the interorgan transport of carbon and nitrogen, the plasma glutamine pool is turning over very rapidly (3). Glutamine tracer kinetic studies in humans have shown that ϳ50% of plasma glutamine is oxidized and that of the remainder, 10 -20% is used for gluconeogenesis, and most of the rest is used for protein synthesis and incorporation into macromolecules (2).Thus far, the irreversible GS 5 inhibitor methionine sulfoximine (MSO) was the tool of choice to interfere with cellular glutamine synthesis. Administration of MSO for 4 -6 days results in a 40 -50% decrease in plasma glutamine levels, a 55-65% decrease in intracellular muscle glutamine, and a 50% increase in muscle ammonia levels (4 -6). An inherent drawback of the...

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Section: Discussionmentioning

confidence: 99%

Glutamine Synthetase in Muscle Is Required for Glutamine Production during Fasting and Extrahepatic Ammonia Detoxification

Hakvoort

Köhler³

et al. 2010

Journal of Biological Chemistry

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“…Its functions in implantation and placentation have not been revealed. Agrin is well known as an essential molecule for maintenance of postsynaptic structures at the neuromuscular junction [15]. Agrin-deficient mice have increased mortality around birth because of respiratory failure so that aggregation of AChR does not occur in the muscle [29].…”

Section: Discussionmentioning

confidence: 99%

“…It has been proven that agrin is secreted by the axonal ends of neuronal cells in the embryonic stage and have an effect on synapse formation by activating muscle specific kinase (MuSK), which is a receptor protein kinase in muscle, and rapsyn, a protein that interacts with AChRs [15]. The localization and function of agrin in the uterus remains to be determined.…”

mentioning

confidence: 99%

Agrin Pathway is Controlled by Leukemia Inhibitory Factor (LIF) in Murine Implantation

Terakawa

Hondo

Sugiyama

et al. 2009

Journal of Reproduction and Development

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Abstract. Agrin is the heparan sulfate proteoglycan (HSPG) that is well known as the molecule that aggregates acetylcholine receptor (AChR) through muscle specific kinase (MuSK) and rapsyn at neuromuscular junctions. HSPGs are spatiotemporally expressed in embryonic and maternal tissues during implantation. The present study examined the role of agrin in the mouse embryo using leukemia inhibitory factor (LIF)-deficient mice, which show complete sterility. Agrin was detected widely in the cytoplasm of uterine luminal epithelial cells at the third day of pregnancy (Day 3) and Day 4. At Day 5, agrin moved to the apical surface of the luminal epithelium. This migration was not found in LIF-deficient mice. AChR was also found in the apical surface of the uterine epithelium at Day 4 and Day 5 in normal mice. LIF-deficient mice did not show this pattern of expression. Only nAChR β1 subunit mRNA was increased at Day 5 in normal mice. Furthermore, acetylcholinesterase was active in the uterine stroma of normal mice throughout the implantation period and was exclusively active in the uterine epithelium at Day 4. Taken together, agrin signaling was activated in the uterus during embryo implantation in the mice. Here, we suggest that the agrin pathway is involved in closure of the uterine epithelium toward placentation.

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“…The main component of the neuromuscular junction -the acetylcholine receptor (AChR) -is initially expressed in developing myofibers also in absence of neural cells, i.e. independent from motoric innervation (Witzemann 2006). The AChR clusters at this stage of myogenesis are located at the central regions of myofibers and this phenomenon known as "prepatterning", marks the development of mature myofibers in myogenesis.…”

Section: Electrical Stimulation and Neurotizationmentioning

confidence: 99%